In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds has been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors.
Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (.mu.), delta (.delta.), sigma (.sigma.) and kappa (.kappa.) receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. Sigma receptors mediate various biological activities.
The existence of the opioid delta receptor is a relatively recent discovery which followed the isolation and characterization of endogenous enkephalin peptides which are ligands for the delta receptor. Research in the past decade has produced significant information about the delta receptor, but a clear picture of its function has not yet emerged. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
Opioid agents frequently are characterized as either agonists or antagonists. Agonists and antagonists are agents which recognize and bind to receptors, affecting (either initiating or blocking) biochemical/physiological sequences, a process known as transduction. Agonists inhibit or suppress neurotransmitter outputs in tissues containing receptors, e.g., inhibiting pain responses, or affecting other output-related phenomena. Antagonists also bind to receptors, but do not inhibit neurotransmitter outputs. Thus, antagonists bind to the receptor sites and block the binding of agonist species which am selective for the same receptor.
Concerning specific receptor ligands, the distinction between delta receptor agonists and antagonists heretofore has been made by their activity in the electrically stimulated mouse vas deferens assay, which typically has been considered the appropriate diagnostic tissue for the delta receptor. By contrast, mu receptor agonists are generally characterized by their activity in the electrically stimulated guinea pig ileum assay.
Only a relatively small number of essentially pure delta receptor-selective agents is known, and with the exception of the delta opioid receptor antagonists disclosed in Portoghese U.S. Pat. No. 4,816,586, all known delta receptor-selective opioid compounds are peptides, including endogenous enkephalins and other endorphins, as well as exogenous peptide analogs. The previously synthesized exogenous peptide analogs have various associated disadvantages in terms of their stability, their potentially suitable delivery routes as administered drug agents, and their in vivo tissue distribution.
Various physiological effects of the known peptide-based opioid ligands have been studied, including: analgesia; respiratory depression; gastrointestinal effects; mental, emotional, and cognitive process function; and mediation/modulation of other physiological processes.
The aforementioned U.S. Pat. No. 4,816,586, issued Mar. 28, 1989 to P. S. Portoghese, discloses various delta-opioid receptor antagonists of specified formula. The disclosed antagonist compounds are formed by fusion of an indole, benzofuran, benzopyrazine, or quinoline ring system, to the C-ring of naltrexone. These compounds are described as possessing a unique opioid receptor antagonist profile, including compounds which are highly selective for the delta opioid receptor.
U.S. Pat. No. 4,518,711 issued May 21, 1985 to V. J. Hruby et al describes cyclic, conformationally constrained analogs of enkephalins. These compounds include both agonists and antagonists for the delta receptor, and are said to induce pharmacological and therapeutic effects, such as analgesia in the case of agonist species of such compounds. The antagonist species of the disclosed compounds are speculated to be useful in the treatment of schizophrenia, Alzheimer's disease, and respiratory and cardiovascular functions.
In addition to the above-described references relating to opioid compounds, the art relevant to the compounds of the present invention includes the polyaryl piperazine compounds described in the various references identified below.
S. Goenechea, et al, in "Investigation of the Biotransformation of Meclozine in the Human Body," J. Clin. Chem. Clin. Biochem., 1988, 26(2), 105-15, describe the oral administration of a polyaryl piperazine compound in a study of meclozine metabolization in human subjects.
In "Plasma Levels, Biotransformation and Excretion of Oxatomide in Rats, Dogs, and Man," Meuldermans, W., et al, Xenobiotica, 1984, 15(6), 445-62, there is disclosed a metabolic study of plasma levels, biotransformation, and excretion of oxatomide.
T. Iwamoto, et al, in "Effects of KB-2796, A New Calcium Antagonist, and Diphenylpiperazines on [.sup.3 H]nitrendipine Binding," Jpn. J. Pharmacol, 1988, 48(2), 241-7, describes the effect of a polyaryl piperazine of specified formula, as a calcium antagonist.
K. Natsuka, et al, in "Synthesis and Structure-Activity Relationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazine Derivatives Having Narcotic Agonist and Antagonist Activity," J. Med. Chem., 1987, 30 (10), 1779-1787, disclose racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives.
European Patent Application No. 458,160 published Nov. 27, 1991 describes substituted diphenylmethane derivatives which are said to be useful as analgesic and antiinflammatory agents, including compounds wherein the methylene bridging group (linking the two phenyl moleties) may have as a substituent on the methylene carbon a piperidinyl or piperazinyl group.
South African Patent Application No. 8604522 published Dec. 12, 1986 discloses N-substituted arylalkyl and aryl-alkylene substituted amino-heterocyclic compounds, including piperidine derivatives, which are described as useful cardiovascular, antihistamine, and anti-secretory agents.
European Patent Application No. 133,323 published Feb. 20, 1985 discloses certain diphenylmethyl piperazine compounds useful as non-sedative antihistamines.
There is a continuing need in the art for improved opioid compounds, particularly compounds which are free of addictive character and other adverse side effects of conventional opiates such as morphine and pethidine.